It is known that mammalian cells quickly respond and adapt to environmental stimuli (for example, mechanical load, metabolic changes, ischemia and reperfusion) by expressing a number of genes. Especially, oxidative stress induced by various external stresses (for example, ischemia followed by reperfusion, ultraviolet burn, and irradiation) is known to play a key role in pathogenesis of cell injury involved, which accelerates inflammation, atherosclerosis, aging, and the like.
In particular, cardiac myocytes express various genes coding for growth factors, cytokines, cell-adhesion molecules, and so on, in response to ischemia/reperfusion to adapt to these stresses, or lead to further cell damage known as reperfusion injury. The threshold of cardiac myocytes to undergo apoptosis seems to be so high to protect these non-division cells from external stresses. For example, only small part of cardiac myocytes can undergo apoptosis even in such a situation of acute myocarditis in which strong expression of Fas on cardiac myocytes and FasL on infiltrating lymphocytes was induced (Non Patent Literature 1). However, there is the only exception of the case, which is reperfusion injury. Reperfusion of ischemic tissue causes massive production of oxygen free radicals, excessive intracellular calcium influx, and neutrophil infiltration, resulting in acute inflammation associated with extensive apoptosis of cells. Because reperfusion-induced apoptotic cell death was not induced by ischemia alone, and could not be prevented by neutrophil depletion (Non Patent Literature 2), it has been proposed that some mechanism triggered by reperfusion mediates the apoptosis signaling pathway, which may precede and be independent of neutrophil infiltration (Non Patent Literature 3).
Eukaryotic translation initiation factor (eIF) 5A is a substance which was identified as a translation initiation factor as its name suggests. It is known that eIF5A is expressed in the cytoplasm, deoxyhypusinated by deoxyhypusine synthase (DHS) (deoxyhypusinated eIF5A), and after that hypusinated by deoxyhypusine hydroxylase (DOHH) (hypusinated eIF5A), and that this hypusinated eIF5A exhibits a cell proliferative action (Non Patent Literature 4). However, it has not been known at all that eIF5A is secreted extracellularly, and what role the secreted eIF5A plays in induction of apoptosis.